The long-term objective of the applicant is to utilize dextran polymers for targeted delivery of drugs and proteins to the liver. This delivery system can be of clinical application when the main site of action of the therapeutic agent is in the liver and/or the presence of the agent in other tissues is associated with undesired effects. The specific purpose of this application is to test the feasibility of such a delivery system by studying the characteristics of hepatic accumulation of fluorescein-labeled neutral dextrans (FDs) in rats. First, the relationship between the MW of dextrans and the extent of their accumulation in the liver and excretion in the urine will be studied after intravenous administration to rats of single 5mg / kg doses of FDs with MWs of 4000 (FD-4), 20 000 (FD-20), 70 000 (FD-70), and 150 000 (FD- 150). Serial serum, urine, and tissue (including liver) samples will be obtained. Second, the dose-dependency of the kinetics of a low (FD-4) and a high (FD-150) MW of FD will be investigated using both in vivo and isolated liver perfusion studies. Various intravenous doses in the range 1-100 mg/kg will be used for in vivo studies, and serial biological samples will be obtained. Additionally, isolated rat livers will be perfused with perfusates containing 1-100 mu g/mL of FDs, and inflow, outflow, bile, and tissue samples will be collected. Third, the time course of the amount of FD-4 or FD-150 in the liver will be delineated in isolated perfused rat livers both during constant infusion of FDs at steady state and also during the post-infusion period. These last experiments will be coupled to metabolism studies of FD-4 and FD-150 using rat liver homogenates to provide data regarding the longevity of FDs in the liver in the presence and absence of the dextran input. The concentrations of FDs in biological samples will be analyzed using a sensitive and specific high-performance size-exclusion chromatographic method which is also capable of detecting alterations in the MW of FDs. Relevant pharmacokinetic parameters will be calculated for both in vivo and in vitro studies to determine the MW-, dose-, and time-dependency of the hepatic accumulation of FDs in rats. These studies will be used as a foundation for future design of hepatically-targeted pharmacotherapeutic agents using dextrans.